N-substituted phenylalkylamines



United States Patent 3,225,098 N-SUBSTHTUTED PHENYLALKYLAMINES WalterKrohs, Bad Soden, Taunus, and Leopold Ther and Gerhard Vogel, Frankfurtam Main, Germany, assignors to Farbwerhe Hoeclrst Alttiengesellsehalitvormals Meister Lucius dz Briining, Frankfurt am Main, Germany, acorporation of Germany No Drawing. Filed July 17, 1962, Ser, No. 210,538(Ilailns priority, application Germany, Italy 19, 1961, F 34,467 7Claims. (Cl. 260-57013) The present invention relates to newphenylalkylamines which are distinguished by analgesic properties and totheir method of manufacture. The present invention further providespharmaceutical preparations having analgesic properties and containingsaid substances as active ingredients.

We have found that phenylalkylamines of the general Formula I in which Rrepresents hydrogen, an alkyl group having from 1 to 4 carbon atoms orthe benzyl group, R represents an alkyl group having from 2 to 4 carbonatoms, R represents a pentyl group or a cylclopentyl group and R and Rrepresent an alkyl group having from 1 to 4 carbon atoms or, togetherwith the combining carbon atom, members of a saturated carbocycle havingfrom 5 to 6 carbon atoms, possess valuable therapeutical properties,particularly analgesic action and that said compounds may be obtained by(a) The reaction of an amine of the general Formula wherein R R have themeanings given above, with a ketone of the general Formula III (III) R.IV

in which R, and R have the meanings given above and X represents aninorganic or organic acid residue, if desired, by means of an agentsplitting off the acid residue;

(c) Heating an amine of the general Formula II given above with analcohol of the general Formula V 3,225,698 Patented Dec. 21, 1965wherein R and R have the meanings given above, and, if desired,splitting oif the alkyl group in the products in which the substituent Rrepresents an alkyl group according to known methods and, if desired,alkylating the products in which R represents hydrogen by means of analkylating agent and, if desired reducing catalytically the products inwhich R represents a benzyl group in order to split off the benzylgroup; and, if desired, converting the basic compounds obtained into thecorresponding addition salts by means of inorganic or organicphysiologically tolerable acids.

The most advantageous method of preparation of the products according tothe invention is to react amines of the general Formula II with ketonesof the Formula III.

The alkyl radicals R R and R may be. the same or different and may bestraight chained or branched. There may be mentioned, for example,methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and sec. butylradicals.

As amines there may be used, for example:

2- 3 -hydroXy-phenyl) -2-pentyl- (3 -butylamine-( 1 2- (3-hydroxy-phenyl) -2-pentyl- (3 -pentylamine-( 1 2- 3 '-hydroXy-pher1yl-2-pentyl- 3 '3 -methylbutylamine-( l 2- (3 '-hydroXy-phenyl) -2-pentyl-3 -3 methylpentylamine-( 1),

2-(3 '-methoxy-phenyl) -2-pentyl-(3 )-butylamine-(1),

2-( 3 '-methoxy-phenyl)-2-pentyl-(3")-pentylamine-(1),

2- 3 -1nethoxy-phenyl -2-pentyl- 3 -3 -methylbutylamine-( l 2- (3'-methoxy-phenyl -2-pentyl-( 3 -3 -methylpentylamine-( 1 2- 3-ethoXy-phenyl -2-pentyl- 3 ")-butylamine-(1),

2- (3 -ethoxy-phenyl) -2 pentyl- 3 ")-pentylamine-(1 2- (3-ethoxy-phenyl -2-pentyl- (3 -3 -methylbutylamine-( 1 2- 3'eth0Xy-phenyl) -2-pentyl- (3 -3 methylpenytlamine-( l),

2- (3 '-hydroXy-phenyl)-2-cyclopentyl-butylamine-(1),

2- 3 -hydroxy-phenyl) -2-cyclopentyl-penty1amine-( l 2- (3'-l1ydroXy-phenyl) -2cyclopentyl-3-methylbutylamine-(l),

2- (3 '-hydroXy-phenyl) -2-cyclopentyl-3-methylpentylamine- 1) 2- (3-rnethoxy-phenyl) -2-cyclopentyl-buty1amine-( 1 2- (3 -methoxy-phenyl-2-cyclopentyl-pentylamine-( 1 2- (3 '-methoxy-phenyl -2-cyclopentyl-3-methylbutylamine-( l 2- (3 -methoxy-phenyl-2-cyclopentyl-3-methylpentylamine-( 1),

2- (3 -ethoXy-phenyl -2-cyclopentyl-butylamine-( l 2- 3 '-ethoXy-phenyl)2-cyclopentyl-pentylamine-( 1) 2- (3 '-ethoXy-phenyl)-2-cyclopenty1-3-methylbutylamine-( 1 2- (3 -ethoXy-phenyl -2-cyclopentyl-3-methylpentylamine-( 1),

2-(3 -benZyloxy-phenyl)-2-cyclopentyl-butylamine-( l),

2- 3 -benzyloXy-phenyl -2-cyclopentyl-pentylamine-( 1),

2- 3 -benzyloXy-phenyl) -2-cyclopentyl3 -methylbutylamine-( 1),

2- 3 -benzyloXy-pl1enyl -2-cyclopentyl-3 -1nethylpentylamine.

As ketone of the Formula III there may be used, for example, thefollowing compounds: acetone, methylethylketone, methylpropyl-ketone,methylbutyl-ketone, met-lb ylisopropyl-ketone, methylisobutyl-ketone,diethyl-ketone, dipropyl-ketone, methylvinyl-ketone,isopropylidene-acetone (rnesityloxide), cyclopentanone orcyclo-hexanone.

The amines of the Formula II to be used as starting substances areadvantageously prepared by hydrogenation of the correspondinglysubstituted cyanides in the presence of catalysts of the 8th group ofthe Mendeleff Periodic System. The cyanides may be prepared by reactingthe correspondingly substituted benzyl-cyanides with sodium amide andalkyl or cyclopentyl halides in a solvent 1mmiscible with water.

The reduction of an amine of the general Formula II in the presence of aketone of the general Formula III may, for example, be effectedcatalytically with the use of metals of the 8th group of the MendeleffPeriodic System, preferably with palladium catalysts. The reaction maybe varied in wide limits and may be adapted to special conditions. Itcan, for example, be carried out in the presence of an excess amount ofketone simultaneously serving as solvent. The reaction is preferablyeffected at a temperature up to 50 C. and under a pressure of hydrogenof 50 atmospheres. When operating accordthe presence of an excess amountof ketone simultaneing to this method, the excess ketone is nothydrogenated to yield the corresponding carbinol and may be recovered.It is, however, also possible to operate without the use of the excessketone and to use another appropriate solvent, for example, methanol.Instead of palladium, nickel catalysts (Raney nickel) may also be used.It is likewise possible to carry out the reduction with the use ofnascent hydrogen, for example, by using aluminum amalgam and alcohol,sodium amalgam, lithium-aluminum hydride or sodium boron hydride. Thereduction, may furthermore, be carried out by electrolysis.

According to another advantageous method of preparing the compounds ofthe invention, the amines of the Formula II may be reacted with theesters of inorganic or organic acids of the Formula IV. There may beused for example, isopropyliodide, sec.butyl-bromide, 3-bromopentane,2-bromo-3-methylbutane, 2-bromo-4-Inethyl-pentane, cyclopentyl-bromide,cyclohexyl-bromide, p-toluenesulfonic acid isoprop-yl-ester, ordi-isopropyl-sulfate.

The reaction is preferably performed by heating the reactants in anappropriate solvent, for example, ethanol, isopropanol, benzene, tolueneor xylene, at temperatures between 80 and 130 C. The heating perioddepends on the temperature and the reactivity of the ester component andusually amounts to 1 to 20 hours. In order to bind the acids that haveformed during the reaction the amine of the Formula II may be used in anexcess of one to several times the molar quantity, and a solventimmiscible with water, in which the amine salt formed during thereaction is insoluble, may be used. For binding the acids formed theremay also be used instead of the excess amine other basic compounds, forexample, sodium bicarbonate, anhydrous sodium carbonate or tertiaryamines, such as triethylamine or diethylaniline. The reaction may alsobe carried out without using solvents by heating both reactioncomponents to temperatures between 80 and 130 C., the use of the aminein a bimolar excess being advantageous.

Another method of preparing the compounds of the invention consists inheating amines of the Formula II with alcohols of the Formula V in thepresence of Raney nickel for a prolonged period of time at temperaturesbetween 100 C. and 120 C. The heating period depends on the structure ofthe starting substances used and is generally between 5 and hours.

For the preparation of the products of the invention in which thesubstituent R represents a hydrogen atom, it is advantageous to preparefirst the corresponding alkoxy or benzyloxy compound according to one ofthe indicated methods. The alkoxy compounds may then be converted in theusual manner, for example by heating with hydrogen chloride, hydrogenbromide, .aluminum chloride or pyridinhydrochloride into thecorresponding hydroxy compounds. If benzyloxy compounds are used asstarting substances, for example2-(3-benzyloxy-phenyl)-2-cyclopentyl-butylamine-(l), the reaction can becarried out in one or two stages of operation. When introducing forexample the radical R4 is introduced according to other methods, forexample, by reacting an amine of the Formula II with an ester of theFormula IV, the benzyloxy group is not affected and if desiredcan besplit oil in a further step of this reaction, for example, by means ofnoble metals of the 8th group of the Mendeleff Periodic System ascatalysts.

On the other hand, if according to one of the abovedescribed methodsthere are obtained products in the formulae of which R represents ahydrogen atom, the hydroxy group can be converted into the methoxy orethoxy group by ethylation in the usual manner, for example withdimethylsulfate or diethylsulfate in an alkaline solution,

The products of the present invention can be converted into thecorresponding acid addition salts by treatment with inorganic or organicacids. For the salt formation the following physiologically tolerableacids may be used: inorganic acids, for example a hydrohalic acid,particularly hydrochloric or hydrobromic acid, sulfuric acid, phosphoricacid, amido-sulfo acid, and organic acids such as acetic acid, propionicacid, oxalic acid, malic acid, succinic acid, lactic acid, maleic acid,furmaric acid, sorbic acid, citric acid, aceturic acid aspartic acid,p-amino-benzoic acid, salicylic acid and ethylenediamine-tetraceticacid.

The analgesic activity of the new products of the invention wasdemonstrated in mice according to the method of Wolfi, Hardy, Goodell,J. Clin. Inv. 19, 659 (1940). When applying this method, the preparationwas administered subcutaneously or orally to a number of mice and theperiod of time in which the animals reacted to the thermal irritationwas examined prior to and after administration of the products. Thismethod was modified in such a way that by a process of all or nothingcertain criteria were used in order to ascertain the percentage ofanimals showing positive response in the test. Thus, relatively exactrelations of the eli ective doses could be found. Upon subcutaneousadministration the lowest ettective dose (dosis etfectiva minima 50) of0.85 milligram/kilogram was ascertained for the N -sec.butyl-2- 3'-hydroxy-phenyl -2-cyc1opentyl-butylamine-(l)-hydrochloride accordingto this method. In comparison with the known 2-dimethylamino-4,4-diphenylheptanone (5)-hydrochloride the lowest elfective dose of thelatter substance amounts to 1.5 milligrams/kilogram on subcutaneousadministration. Upon subcutaneous administration the present preparationthus proved to be twice as potent as the knownZ-dimethylamino-4,4-diphenylheptanone (5 )-hydrochloride. When given tomice which are in a state of excitement caused by subcutaneous injectionof l-phenyl-Z-methylaminopropane hydrochloride according to the methodby Ther (Deutsche Apotheker-Zeitung 1953, p. 292), the abovementionedcompound showed a distinctly sedative action.

Examination methods in the goldhamster (Mesocricetus auratus) accordingto Ther, Vogel and Werner, Arzneimittelforschung 9, 351 (1959), andexamination methods in the cotton rat according to Vogel and Ther,Arzneimittelforschung 10, 806 (1960), have demonstrated sedativeneuroleptic action.

Toxicity tests have revealed that the products of the present inventionare to be considered harmless.

For example, in mice the lethal dose 50 for N-sec.butyl-2-(3-hydroxy-phenyl)-2 cyclopentyl butylamine-(l)- hydrochloride is 30milligrams/kilogram in the case of intraveneous injection, 250milligrams/kilogram in the case of subcutaneous injection and 900miligrams/kilogram in the case of oral administration. Long-termtoxicity tests showed that the compound when administered orally to dogsfor 28 days in a dose of milligrams/kilogram was tolerated withoutcausing pathologic symptoms in the clinical picture and in post mortemexaminations.

In clinical trials N-sec.butyl-2-(3-hydroxy-phenyl)-2-cyclopentyl-butylamine (1) hydrochloride revealed a marked analgesicaction when administered in a dose of 2 to 4 milligrams. The products ofthe present invention can be applied either in form of the free aminesor in the form of their addition salts with physiologically tolerableacids as analgesic medicaments, if desired, in admixture with suitablesolid or liquid pharmaceutical carriers such as water, vegetable oils,starch, lactose or talcum, if desired, with auxiliary agents such asstabilizing, preserving and emulsifying agents. The compounds arepreferably administered in the form of solutions or suspensions forinjections, and of tablets, clragees, capsules and suppositories.

For parenteral administration a dose of 1 to mg. may be taken intoconsideration and for oral administra tion a dose of 5 to 50 milligrams.

The following examples serve to illustrate the invention, but they arenot intended to limit it thereto:

EXAMPLE 1 N-sec.butyl-2-(3'-meth0xy-phenyl) -2-pentyl-(3)-butylamine-(1) grams of 2-(3-methoxy-pheny1)-2-penty1-(3")-butylamine-(1) and 150 grams of methylethylketone were hydrogenated at50 C. in the presence of palladium as catalyst until the hydrogen ceasedto be absorbed. After separation from the catalyst and elimination ofthe excess methylethylketone by distillation N-sec.butyl-2-(3-methoxy-phenyl)-2-pentyl (3") butylamine-(1) was obtained in aquantitative yield. The corresponding fumarate melted at 107 C.

The 2- 3 -methoxy-phenyl -2-pentyl- 3 -butylamine- (1), boiling point=148152 C. serving as starting sub stance was obtained by hydrogenationof (3-methoxyphenyl) -ethylpentyl- 3 -acetonitrile (boiling point148-150 C.) prepared by reacting (3-methoxy-phenyl)- ethyl-acetonitrilewith sodium amide and 3-bromopentane.

EXAMPLE 2 By heating under reflux theN-sec.buty1-2-(3-methoxyphenyl)-2-pentyl-(3)-butylamine-( 1) withhydrobromic acid of 48% strength for 8 hours, the methyl group was splitoff. The N-sec.butyl-2-(3'-hydroxy-phenyl)-2-pentyl-(3")-butylamine-(1)was obtained in a quantitative yield and formed a fumarate which meltedat 167 C.

EXAMPLE 3 N-isopr0pyl-2 (3-meth0xy-phenyl) -2-cycl0pentylbutylamine-(1)(a) 20 grams of 2-(3-methoxy-phenyl)-2-cyclopentylbutylamine-(1) werehydrogenated in 100 grams of acetone according to the prescriptionsgiven in Example 1. The N-isopropyl-2-(3'-methoxy-phenyl)-2cyclopentylbutyl-amine-(l) was obtained in a quantitative yield. Itshydrochloride melted at 145 C.

(b) The same compound was obtained by heating for 15 hours at C.2-(3'-methoxy-phenyl)-2-cyclopentylbutylamine-(1) with excessisopropanol and a large quantity of Raney nickel.

(c) The same compound was obtained by heating for 3 hours at 100 C.2-(3'-methoxy-phenyl)--2-cyclopentylbutylamine-(1) with one mol ofdiisopropyl sulfate.

EXAMPLE 4 N -sec.butyl-2- (3 '-methoxy-phenyl-2-cycI0pentylbutylamine-(1) (a) 300 grams of2-(3'-methoxy-phenyl)-2-cyclopentylbutylamine (1) were hydrogenated in750 grams of methylethylketone according to the prescriptions given inExample 1. The N-sec.butyl-2-(3'-methoxy-phenyl)-2-cyclopentyl-butylamine-( 1) was obtained in a quantitative yield. Itshydrochloride melted at C.

(b) The same compound was obtained by hydrogenating 2- 3 -methoxy-phenyl-2-cyclopentyl-butylarnine-( 1 with methylvinylketone and palladium ascatalyst at 50 C. until the hydrogen ceased to be absorbed.

The 2-(3-methoxy-phenyl)-2-cyclopentyl butylamine- (1), boiling point=174176 C., serving as starting substance was obtained by hydrogenationof (3-methoxyphenyl) ethyl cyclopentyl acetonitrile (melting point=154-156 C.) prepared by reacting (3-methylphenyl)-ethylacetonitrilewith sodium amide and cyclopentylbromide.

EXAMPLES 5-9 From 2 3 -methoxy-pher1yl -2-cyclopentyl-butylamine- (1)there were obtained the following compounds according to the processdescribed in Example 1 by the hydrogenation with ketones:

(5 With methylisopropylketone there was obtained theN-[3"-methyl-butyl-(2")]-2-(3 methoxy phenyl) 2-cyclopentyl-butylamine-(l). Melting point of the hydrochloride: 131 C.

(6) With methylpropylketone there was obtained theN-pentyl-(2)-2-(3-methoxy-phenyl) 2 cyclopentylbutylamine-(1). Meltingpoint of the hydrochloride 200 C.

(7) With diethylketone there was obtained the N-pentyl- (3 -2- 3-methoxy-phenyl -2-cyclopentyl butylamine- (1). Melting point of thehydrochloride 155 C.

(8) With cyclopentanone there was obtained the N- cyclopentyl-2- 3-methoxy-phenyl -2-cyclopentyl butylamine-(1). Melting point of thehydrochloride 230 C.

(9) With cyclohexanone there was obtained the N-cyc1ohexyl-2-(3-methoxy-phenyl)-2 cyclopentyl butylamine-(1). Meltingpoint of the hydrochloride C.

EXAMPLES 10-17 By heating the 3-methoxy compounds described in theExamples 3 to 9 for 8 hours under reflux with hydrobromic acid of 48%strength the methyl group was split 01f, while the correspondinghydroxphenyl derivatives were formed. The following products wereprepared in this manner.

10) N-isopropyl-Z- 3 -hydroxy-phenyl -2-cyclopentylbutylamine-(1);melting point of the hydrochloride: 206 C.

11a) N-sec.butyl-2-(3-hydroxy-phenyl) -2-cyclopentylbutylamine-(1);melting point of the hydrochloride: 178 C.

(111)) The same compound was obtained by hydrogenating at 50 C. the2-(3'-hydroxy-phenyl)-2-cyclopentyl butylarnine-(l), which had beenobtained by demethylation of the corresponding methoxy compound withhydrobromic acid of 48% strength and which formed a fumarate melting at150 C., with methylethylketone and palladium as catalyst.

(12) N-[3"-methyl-butyl-(2")] 2 ('3'hydroxyphenyl)-2-cyclopentyl-butylamine-(1); melting point of thehydrochloride: 164 C.

(13) N-pentyl-(2)-2-(3-hydroxy-pheny1) 2 cyclo- 7 pentyl-butylamine-(lmelting point of the hydrochloride: 212 C.

(14) N-pentyl-(3")-2-(3'-hydroxy-phenyl) 2 cyclopentyl-butylamine-( 1);melting point of the hydrochloride: 184 C.

(15) N-cyclopentyl-2-(3'-hydr0Xypheny1)-2 cyclopentyl-butylamine-( 1);melting point of the hydrochloride: 209 C.

(16) N-cyclohexyl-Z-(3-hydroXy-phenyl)-2 cyclopentyl-butylamine-(l);melting point of the hydrochloride: 236 C.

(17) N-sec.butyl-2-(3'-cthoxy-phenyl)-2 cyclopentylbutylamine-(1) wasobtained by causing diethylsulfate in alkaline solution to act onN-secbutyl-Z-(3'-hydroxyphenyl)-2-cyclopentyl-butylamine(1) obtainedaccording to Example 11.

EXAMPLE 18 N-sec.butyl-2-(3'meth0xy-phenyl) -2-cycl0pentylpentylamine-(I16 grams of 2-(3'-methoxy-phenyl)-2-cyclopentyl-pentylamine-( 1) werehydrogenated and worked up in 150 grams of methylethylketone accordingto the prescription given in Example 1. TheN-sec.butyl-2-(3-methoxyphenyl)-2-cyclopenty1-pentylamine-(1) wasobtained in a quantitative yield. Its hydrochloride melted at 127 C. The2-(3'-methoxy-phenyl)-2-cyclopentyl pentylamine- (1) (boiling point=178-l8O C.) serving as starting substance was obtained by hydrogenationof (3-methoxyphenyl) propyl cyclopentyl acetonitrile (boiling point=168170 C.). The latter compound can be prepared from3-methoxybenzylcyanide, sodium amide and propyl bromide and bysubsequent reaction of the (3 methoxy phenyl) propylacetonitrile(boiling pint =134135 C.) obtained with sodium amide andcyclopentylbromide.

EXAMPLE 19 N -sec.butyl-2- (3 -hydr0xy-phenyl -2-cycl0pentylpentylamine-(J By heating under reflux theN-sec.buty1-2-(3-methoxyphenyl)-2-cyclopentyl-pentylamine-( 1) withhydrobromic acid of 48% strength for 8 hours, the methyl group was splitoff. The N-sec.butyl-2-(3-hydroxy-phenyl)-2-cyclopentyl-pentylamine-(l)was obtained in a quantitative yield. Its hydrochloride melted at 228 C.

We claim:

1. The compounds selected from the group consisting of (1)phenylalkylamines of the general Formula I in which R is selected fromthe group consisting of hydrogen, an alkyl group having from 1 to 4carbon atoms and the benzyl group, R represents an alkyl group havingfrom 2 to 4 carbon atoms, R is selected from the group consisting of apentyl group and a cyclopentyl group, and R and R are selected from thegroup consisting of an alkyl group having from 1 to 4 carbon atoms and,together with the combining carbon atom, members of a saturatedcarbocycle having from 5 to 6 carbon atoms, and (2) addition salts ofsaid compounds with physiologically compatible acids.

2. N-secbutyl-Z-(3'-hydroXy-phenyl) 2 pentyl-(3)- butylamine- 1 3.N-isopropyl-2-(3'-methoXy-phenyl) 2 cyclopentylbutylamine-( 1).

4. N-isopropyl-Z-(3'-hydroxyphenyl) 2 cyclopentylbutylamine- 1 5.N-sec.butyl-2-(3'-hydroxy-phenyl) 2 cyclopentylbutylamine- 1 6.N-pentyl-(3")-2-(3-hydroxy-phenyl) 2 cyclopentyl-butylamine- 1) 7.N-sec.butyl-2-(3-hydroXy-pheny1) 2 cyclopentylbutylamine-( 1-hydroch1oride.

References Cited by the Examiner UNITED STATES PATENTS 2,590,079 3/1952Abell et al. 260-570.8 2,597,247 5/1952 Kerwin 260-5708 2,742,397 4/1956Ott 16765 2,884,455 4/1959 Robertson 260-5708 3,036,954 5/1962 Robbins16765 FOREIGN PATENTS 488,303 11/ 1952 Canada.

OTHER REFERENCES Mndzhcoyan et al.: Chemical Abstracts, volume 54, page10910 (1960).

Weston et al.: Journal American Chemical Soc., volume 65, pages 6747(1943).

Woods et al.: Journal Organic Chemistry, volume 19, pages 12905 (1954).

CHARLES B. PARKER, Primary Examiner. MORRIS O. WOLK, Examiner.

1. THE COMPOUNDS SELECTED FROM THE GROUP CONSISTING OF (1)PHENYLALKYLAMINES OF THE GENERAL FORMULA I